Disease Modifying Therapies in Spinal Muscular Atrophy: Preclinical Products

The therapies that are being developed for spinal muscular atrophy (SMA) generally fall into two categories: those that aim to increase levels of survival motor neuron (SMN) protein and those that are SMN-independent.1 The therapies that aim to increase SMN protein levels do so by modulating the transcription of SMN2, by promoting the production of full-length SMN protein, or through SMN1 gene replacement therapy. SMN-independent approaches work through several different mechanisms: targeting processes downstream of SMN, employing neuroprotective strategies, or focusing on the improvement of muscle function. 

Increasing SMN Protein: Preclinical Findings

While there are several molecules aimed at increasing SMN protein levels that are currently being tested through clinical trials, there is a significant amount of preclinical research focused on SMN gene replacement therapy. Gene replacement therapy in SMA is based on the idea that because SMA is caused by the loss of the SMN1 gene, it should be able to be reversed if a normal copy of the gene replaces the faulty copy.1 In practice, the adeno-associated viral vector (AAV) has led to significant success in delivering the SMN1 gene to cells of the central nervous system. 

AAV serotype 9 (AAV9) can cross the blood-brain barrier, facilitating easy delivery and allowing for the therapy to be administered noninvasively.2 Preclinical work has shown that AAV9 encoding SMN1 can fully reverse severe SMA in a variety of animal models, improving motor function and neurophysiology, and significantly extending the lifespan.1,3 These promising preclinical findings have led to the development of other potential AAV treatments that are being tested in clinical trials.  

While AAV strategies for gene therapy are promising in their potential to help SMA patients, more research is needed to determine the effectiveness of the long-term expression of AAV. Luckily, AAV expression has been shown to last for decades in other diseases, and there have been no reports of clinical worsening in SMA during the first two years of gene therapy.14,15 AAV thus appears to be a promising approach for helping those with SMA. 

SMN-Independent Strategies: Preclinical Findings

The primary strategy for neuroprotection against SMA aims to enhance the survival and functioning of motor neurons. Olesoxime, which is a cholesterol-like compound, has provided successful results in preclinical research and so is currently being investigated in clinical trials.1,4 While there are molecules aimed at improving muscle function that are also being tested in clinical trials, there are some molecules in this category that are still undergoing preclinical experimentation. 

Rho kinase (ROCK) inhibitors, for instance, have shown therapeutic promise in mouse models of SMA.5,6 Studies on these molecules, which include fasudil and Y-27632, have been based on evidence that RhoA and ROCK are involved in SMA pathogenesis in the spinal cord in animal models.1 Other molecules undergoing preclinical research for their potential to improve muscle function include quercetin, an antioxidant flavonoid, and STL-182, which is a small molecule that is available orally.7,8

Cell-based therapies offer another SMN-independent approach that is currently at the preclinical stage. Stem cells that have been implanted intrathecally into the cerebrospinal fluid or directly into the spinal cord have improved SMA in mouse models of the disease.9–13 Future work in this area will likely explore combination approaches where stem cells are used to complement SMN-based strategies in the hopes of optimizing therapeutic efficacy in those with SMA. 


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